Research at the **Sylvester Comprehensive Cancer Center**, part of the **University of Miami Miller School of Medicine**, has revealed promising results for a new combination therapy aimed at treating hormone-resistant, estrogen receptor-positive (ER+) breast cancer. In preclinical studies, this innovative approach successfully shrank tumors, reduced the number of cancer stem cells, and reprogrammed the surrounding immune environment to be less conducive to cancer growth. The findings, published in **Science Translational Medicine**, demonstrate significant potential for improving patient outcomes.
The cornerstone of treatment for ER+ breast cancer has long been endocrine therapy. However, many patients eventually develop resistance to established medications such as **tamoxifen** and **fulvestrant**, leading to poorer health outcomes. The new research sheds light on the mechanisms behind this resistance and suggests ways to counteract it by targeting specific cellular components within breast cancer cells.
Understanding Resistance Mechanisms
To investigate the underlying causes of hormone resistance, the research team focused on the tumor microenvironment, creating two preclinical models of ER+ tumors resistant to endocrine therapy. The tumor microenvironment, often described as the “neighborhood” surrounding a tumor, consists of various cells that can either promote or inhibit cancer growth. Within this environment, **tumor-associated macrophages** (TAMs)—a specific type of immune cell—were found to play a crucial role.
Researchers identified a particular subtype of TAMs, characterized by proteins **CD163** and **PD-L1**, that were more prevalent in patients whose tumors exhibited resistance to tamoxifen. PD-L1 is a protein that enables cancer cells to evade detection by the immune system. According to **Rumela Chakrabarti**, Ph.D., the study’s senior author and co-director of Sylvester’s Surgical Breast Cancer Research Group, “These macrophages act like bodyguards for the cancer cells, helping them survive treatment.”
Understanding how these macrophages are recruited to the tumor environment is vital. The study revealed that the signaling molecule **DLL1**, produced by cancer cells, acts as a beacon, attracting macrophages via a pathway dependent on **CCR3/CCL7**. Once inside the tumor, these macrophages help sustain cancer stem cells—cells that are particularly resilient and capable of regenerating tumors, making them difficult to eliminate with standard therapies.
In both preclinical studies and patient-derived samples, elevated levels of **DLL1** and PD-L1+ TAMs were strongly associated with resistance to tamoxifen and fulvestrant. Patients exhibiting higher counts of these immune suppressive macrophages showed worse survival rates.
Promising Results from Combination Therapy
To tackle the challenge of hormone resistance, the research team tested a new combination therapy. By administering antibodies that block both DLL1 and PD-L1, in conjunction with low-dose tamoxifen, researchers achieved notable success. The combination not only shrank tumors but also reduced the number of cancer stem cells and altered the immune environment to be less supportive of cancer proliferation.
“This triple therapy approach could be transformative for patients whose cancers no longer respond to standard hormone treatments,” said Chakrabarti, who also serves as an Associate Professor of surgery at the Miller School. “It’s about hitting the cancer from multiple angles at once.”
While the findings are promising, researchers acknowledge that further development is necessary before this therapy can be implemented in clinical settings. Extended in vivo modeling and pilot clinical trials will be essential. “Our models are robust, but human tumors are even more complex,” Dr. Chakrabarti cautioned.
The interplay between cancer cells and their microenvironment is crucial for advancing next-generation therapies. This research underscores the importance of considering not just the tumor itself, but the entire ecosystem that supports it. Chakrabarti emphasized, “Every breakthrough brings us closer to a future where breast cancer is not just treatable, but truly manageable for every patient.”
As the research progresses, the team remains committed to making significant strides toward that future in the coming years. For more information, refer to the study by **Shailesh Singh et al.**, titled “DLL1-responsive PD-L1+ tumor-associated macrophages promote endocrine resistance in breast cancer,” published in **Science Translational Medicine**.
DOI: 10.1126/scitranslmed.adr6207.